The peptide analogues of this invention are useful in treating various diseases caused by an excess of the naturally occurring peptide and in treating peptide-dependent and peptide-secreting tumors. One example of this invention relates to the use and synthesis of humoral hypercalcemic factor (HCF) analogues useful for inhibiting the action of HCF both in vivo and in vitro.
Investigators have isolated and obtained partial amino acid sequences of peptide derived from several different human tumors (lung squamous carcinoma, renal cell carcinoma, and breast carcinoma). J. M. Moseley et al., Proc. Natl. Acad. Sci. U.S.A. 84, 5048 (1987); G. J. Strewler et al., J. Clin. Invest., 80, 1803 (1987); A. F. Stewart et al., Biochem. Biophys. Res. Commun. 146, 672 (1987); M. Mangin et. al., Proc. Natl. Acad. Sci. U.S.A., 85, 597 (1988). One group published the putative full-length peptide structure (141 amino acids) based on the complementary DNA (cDNA) nucleotide sequence. L. J. Suva et al., Science 237, 893 (1987).
Human "humoral hypercalcemic factor" (hHCF) is considered to be related in biological effects to parathyroid hormone (PTH). HCF shows considerable homology to the biologically critical NH.sub.2 -terminal region of PTH. However, there are significant differences in the peptide sequences between PTH and HCF, and this new factor appears to be the product of a different gene. L. J. Suva et al., Science 237, 893 (1987). The differences in sequence between HCF and PTH suggest that HCF may have a specific receptor on non-PTH target tissues, although none have been reported to date. However, with the significant homology between HCF and PTH in the amino-terminus, both peptides might also interact with the HCF receptor and therefore antagonists effective at the PTH receptor may also be effective at the HCF receptor.
Previously, it had been proposed that tumors could secrete PTH ectopically and cause hypercalcemia of malignancy. Several studies demonstrated that a PTH-like factor, physicochemically and immunologically distinct from PTH, is secreted by tumor cells. S. B. Rodan et al. J. Clin. Invest. 72, 1511 (1983); A. F. Stewart et al., Proc. Natl. Acad. Sci. U.S.A., 80, 1454 (1983); G. J. Strewler et al., J. Clin. Invest. 71, 769 (1983). However, messenger RNA for PTH was not found in such tumors. It was also known that this PTH-like factor stimulates adenylate cyclase in PTH target cells, and that this activity can be inhibited by PTH antagonists. Thus, it is presently considered that HCF is a factor that is responsible for hypercalcemia of malignancy by its secretion from the tumor and its altering effect on calcium metabolism.
It is, therefore, an object of the present invention to provide antagonists of HCF. If a peptide analogue of HCF could be constructed which would bind with the cell surface receptor of HCF with equal or greater affinity than the naturally occurring peptide, then the peptide analogue could be used to block the effect of the naturally occurring peptide. Thus, it is also an object of the present invention to provide peptide analogues useful for the treatment of hypercalcemia of malignancy.
Another object of the present invention is to provide novel HCF analogues. Other objects of the present invention are to provide methods of inhibiting the action of HCF through the administration of novel HCF analogues. Still another object of the invention is to provide HCF analogues wherein amino acid modifications result in binding to the cell surface receptors without activating a second messenger molecule. The above and other objects are accomplished by the present invention in the manner more fully described below.